9
strategy for intraspinal plexus lesions is today limited by several conditions:
(1) There is a rapid death of nerve cells after the avulsion trauma.
(2) There is no sensory recovery or afferent feedback.
(3) There is non-specific reinnervation with synergism and deficient hand recovery.
Rapid death of nerve cells after avulsion trauma
There is considerable death among nerve cells after a severe nerve injury, thus obviously interfering with the possibility to restore function by means of surgery. The exact mechanism behind injury-induced neuronal death is not known and appears to be multifac-tor. Trophic deprivation and glutamate-mediated excitotoxicity can cause ischemic as well as apoptotic cell death. Several substances have been tested and found to curtail neuronal death. Regarding motoneurons, there is a rapid retrograde cell death amounting to about 80% after spinal nerve root avulsion injury. Acascade of molec-ular events, where glutamate and calcium have been claimed to play major roles in ischemic cell death, follows such injuries. A possibility to maintain motoneurons after such an injury would be to provide antagonists to glutamate release by blocking NMDA receptors, e.g.
with riluzole (Doble 1996), and to prevent intracellular overload of calcium by inhibiting L-type voltage-gated calcium channels, e.g.
with nimodipine (Mattsson et al. 1999).
Motoneurons seem to be highly dependent on interactions with the periphery and supply of trophic molecules, particularly those derived from Schwann cells. This supply is lost after spinal root avulsion injury, which therefore has a detrimental effect on neu-ron survival through apoptotic cell death. Key trophic factors for both motor and sensory neurons are the brain-derived neurotrophic factor (BDNF) and the glial cell line–derived neurotrophic factor (GDNF). These substances will obviously be supplied “naturally”
after reimplantation surgery (Bergerot et al. 2004). “Artificial” appli-cation of these substances at the avulsion site by osmotic pumps (Li et al. 1995), for instance, or directly to the injured motoneurons through the virus vector technique (Blits et al. 2004), can rescue
motoneurons at least in the short term as well as enhance neurite outgrowth (Novikov et al. 1997).
In a recent study, it was shown that a combination of growth factors and substances that inhibits glutamate release, e.g. riluzole, has a most advantageous effect (Bergerot et al. 2004). Such a com-bination will obviously interfere with apoptotic as well as ischemic cell death, but there is also a synergistic effect from the combined treatment with those substances, leading to a persistent amelio-ration of motoneuron death together with increased synthesis of neurotransmitters — hence, restoration of function. In tests assessing different aspects of recovery, close to normality was noted (Bergerot et al. 2004). Single-treatment therapies proved ineffective at rescuing all motoneurons from cell death or at restoring functional recovery.
Combination therapies proved to be far more effective and offered a potential new treatment strategy for avulsion-injury patients. In the future, a combination of substances that interferes with apop-totic and necrotic neuronal death as well as augments regeneration is most likely to be used in adults, and is also certainly to be indi-cated in severe cases of obstetric plexus injury where surgery, for many reasons, must be postponed for some time.
Cell replacement therapy, i.e. to supplement the disappearing or dead neurons with immature cells or undifferentiated cells, can hypothetically augment recovery in cases where neuronal cell death has depleted the motoneuron population. This might appear as the only option, particularly in cases considered for surgery late (over 1 month) after their injury. The use of stem cells for such neuronal replacement therapy, however, remains dubious, although it is pos-sible in culture dishes to direct such undifferentiated cells to show characteristics of motoneurons. Previous experiments where embry-onic motoneurons were grafted into the spinal cord showed lit-tle signs of integration and functional improvement (Clowry and Vrbova 1992).
No sensory recovery of afferent feedback
It is currently not possible to reconstruct the afferent or sensory path-ways, which are obviously necessary for a full recovery. The first
part of the regrowing motor axons and the last part of the sensory dorsal root ganglion axons have to negotiate the elongation in the hostile CNS tissue. This is obviously possible to some extent for the motoneuron axons, but not at all for the sensory axons except in cases where growth of dorsal root axons has been reported after NT-3 induced regeneration (Ramer et al. 2000; Ramer et al. 2001).
A major problem is the nonpermissive environment in the spinal cord or CNS to axonal elongation or regrowth after injury. Post-injury cellular response or gial cell scarring and the occurrence of growth-inhibitory substances derived from degrading central ner-vous myelin, as well as substances such as semaphorins appearing as secreted and membrane-bound proteins, are thought to contribute to this situation (see review by Fawcett and Asher 1999). A spe-cific gene, termed nogo, and the proteoglycan NG2 have also been implicated in this process. The role of these molecules is, however, currently revised from being considered exclusively inhibitory to be more of guidance cues or “antiarborisation” substances restricting nerve fibres to particular pathways (Morgenstern et al. 2003; Raisman 2003).
The development of molecular biology and the description of var-ious growth-promoting and growth-inhibitory molecules have gen-erally increased the knowledge of subcellular events during nerve injury, degeneration, and regeneration. There has been a great deal of enthusiasm for anticipated improved regeneration of function after injury in the PNS and CNS, applying new molecular therapy derived from these studies. However, there have been little, if any, clinical applications as yet from these endeavours.
In the highly disorganised tissue or scar that follows an injury in the spinal cord or CNS, the experimental strategies to overcome the impediment to regeneration are molecular and cellular strategies, as well as by artificial conduits to bridge the scar region. The use of biochemical agents — including the use of antisense sequences to block the production of the key inhibitory protein and administra-tion of, for instance, chondroitinase enzyme to degrade its funcadministra-tional elements — has been used with some success (Bradbury et al. 2002).
A possibility to enhance growth within the spinal cord is to offer
conduits that are permissive, such as PNS grafts or artificial conduits with qualities that could promote growth. As an artificial conduit, a composite neural guide consisting of a biodegradable carrier (e.g. a soluble glass, with minimal adhesion or fibrosis and full absorption) that contains a microfibrous protein core for cellular-level guidance (e.g. fibronectin) can be used. The effect of the protein-based cell-guidance core has been described (Priestly et al. 2002).
The inability of the dorsal root ganglion neurons to negotiate elongation across the PNS–CNS transitional region at the dorsal root–spinal cord junction is notorious (Carlstedt 1985; Ovelmen-Levitt 1988). Efforts to promote sensory regeneration into the spinal cord are still at the experimental stage, as only now do we have a clearer understanding of the mechanisms that limit regenera-tion in the spinal cord. This has led to strategies that aim to minimise the deleterious effects of trauma and scar formation, or minimise the influence of inhibitory molecules, and maximise and promote trophic support for axonal regeneration by sensory neu-rons (Priestley et al. 2002). An elegant concept is that of cell therapy, which is used to promote the re-establishment of permissive cellular bridges in the spinal cord lesion and thereby create a situation that occurs spontaneously in the peripheral nerve after injury. Experi-ments with Schwann cells (Li and Raisman 1994), and more suc-cessfully with olfactory ensheathing cells (OECs) (Li et al. 1997), have resulted in the functional return of lesioned spinal cord tracts (Li et al.
2003). Such cells have recently been used for regrowth of dorsal root axons into the spinal cord (Li et al. 2004). At the reconstituted dorsal root–spinal cord interface, the OECs formed a ladder-like bridging structure of astrocytic processes, allowing the elongation of dorsal root axons. In addition to the regenerative effect these cells have on the regrowing axons, it was also demonstrated in this study that the OECs are able to reconstruct an anatomical pathway along which the axons can grow. Such reconstruction is a complex histogenetic event requiring the OECs to interact with both Schwann cells of the PNS part of the root and with astrocytes of the spinal cord, forming a tissue bridge along which axons can grow from the severed root
into the spinal cord (Li et al. 2004). This cellular therapy is possible in cases of dorsal root avulsion injury for recovery of connectivity.
Another, and the most important, consequence of lost sensory connection with the spinal cord is the excruciating pain sustained by patients with root avulsion injury. Pain is proportional to the number of roots avulsed and is considered to depend on sponta-neous hyperactivity in spinal cord cells (Guenot et al. 2003). Sur-gical repair strategies that promote functional motor regeneration by means of nerve transfers, as well as by spinal cord reimplan-tation of avulsed ventral roots, alleviate pain sensation just prior to the onset of voluntary movements (Berman et al. 1996; Berman et al. 1998; Carlstedt et al. 2000). The mechanism underlying pain diminution is unknown, but probably involves CNS plasticity. The pharmacological management of this injury is empirical and there is no current consensus as to how to treat these patients, as the underly-ing molecular events that occur followunderly-ing avulsion injury are poorly understood.
Several mechanisms may contribute to this pain. Ischemia and excitotoxicity, due to an imbalance of excitatory and inhibitory mech-anisms, are likely to be major contributing factors. Degenerating primary afferents will release glutamate and other excitatory trans-mitters into the extracellular environment, thereby overexciting neu-rons. Altered levels of voltage-gated sodium channels, which are involved in the generation and propagation of action potentials, are thought to be important, as recent evidence shows that they are upregulated in spinal cord neurons in cases of neuropathic pain after spinal cord injury (Hains et al. 2003). Glial cells have recently also been shown to play a role in the production of neu-ropathic pain. Microglia might induce pain, whilst astrocytes main-tain the pain (Watkins and Maier 2003). Substances that interfere with sodium channels inhibiting glutamate release, such as riluzole (Bergerot et al. 2004), could be an adjunct to dorsal root reconnection to the spinal cord possibly by cellular treatment for the alleviation of pain.
Nonspecific reinnervation with synergism and deficient hand recovery
There is a lack of direction of growth after all types of nerve surgery, particularly after the most proximal nerve or spinal cord repair. The nerve cells within the spinal cord, if offered a peripheral nerve con-duit, will take any opportunity to extend processes and obviously try to reinnervate the first or most proximal target. There is a non-specific recruitment of spinal cord motoneurons into the implanted PNS graft, for instance phrenic neurons, and there is a tendency to reinnervate the most proximal muscles first. This will obviously result in synergism and hyperreinnervation proximally, but deficient distal reinnervation.
The most conspicuous effects of nondirectional growth of motoneurons after intraspinal repair and spinal cord reimplanta-tion of avulsed ventral roots are the phenomena of “breathing arm”
and flexor–extensor muscle cocontraction, which conspire against useful recovery and effective distal limb or hand function. This is an obvious disadvantage, which depends on the nondirectional growth within the PNS rather than on the lack of spinal cord regeneration.
Unfortunately, such synkinesis seems today impossible to correct once it is established (Roth 1983). The regeneration of axons into inappropriate pathways is a major contributing factor to the failure of full functional restitution after nerve repair.
In order to augment recovery, guided tissue regeneration is a pro-cedure expected to improve repair. By using biodegradable artificial conduits, axonal regrowth and restoration of nerve trunk continuity is achieved similar to what is seen after an autologous nerve graft, but the outcome is not superior to conventional repair (Giardino et al. 1999). Motor recovery, for instance, depends on the accuracy of the direction of growth and reconnection with the original mus-cles. Factors contributing to a preferential motor reinnervation of motor axons have been described (Brushart and Seiler 1987; Madi-son et al. 1999). Augmentation in the specificity of regeneration has been reported after using electrical current (Al-Majed et al.
2000), a technique which also has the advantage of accelerating
regrowth. This physical strategy to improve recovery will no doubt be followed in the future by molecular treatments, when more knowledge about specific neuron trophic substances has been achieved.
The root avulsion injury is a limited spinal cord injury that interrupts defined populations of neurons, i.e. the “final com-mon pathway” for motor command and the sensory pathway for the peripheral sensory neurons. Patients with such spinal cord injuries from brachial or lumbosacral plexus injuries, including cauda equina lesions, have recovered function from the reimplan-tation spinal cord surgery. This relatively less complicated injury, compared to a “classical” transverse spinal cord lesion, is obviously advantageous regarding chances for recovery.
The conus medullaris is the finely tapered distal or caudal end of the spinal cord. Cauda equina and conus medullaris forms of spinal cord injury relate to functions served by the sacral outflow, caus-ing flaccid paralysis or paraplegia, autonomic dysfunction with an atonic bladder, and often severe intractable pain. A transverse lesion of the conus medullaris would mostly affect the lower motoneurons and CNS parts of the peripheral sensory neurons, together with ner-vous control over bladder and bowel function. A transverse caudal spinal cord injury at conus level has therefore many similarities with the root avulsion or the longitudinal type of spinal cord injury, and could in the future be considered for a similar type of surgical strat-egy. Avulsed roots would be implanted cranial to the site of the transverse spinal cord lesion in order to reverse lower extremity paralysis with return of locomotion, and reinnervate pelvic targets to reverse bladder and bowel dysfunction. Experimental surgery has been performed that has demonstrated functional return after such procedures (Liu et al. 1999; Tadie et al. 2002).
This book has described the first step in the direction to treat severe intraspinal nerve and spinal cord injuries. In order to reach further, to recover useful function and to alleviate pain, it is of course necessary to pursue research and development of basic and clin-ical science. Surgclin-ical and imaging refinements are also obligatory
to achieve a full or near-normal functional restitution after brachial plexus and lumbosacral plexus avulsion injuries with minimal risks and efforts for the patient. A number of already available pharma-ceutical substances, molecular products, and cellular therapies will be applied in the future to not only continue the achievement of recovery of injuries at the spinal cord surface, but also help find a cure for the more complete spinal cord injuries.
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Index
nogo, 170
aberrant axons, 105
aberrant muscle reinnervation, 143 accessory nerve, 43, 116
acetylcholin, 31
adeno-associated viral (AAV) vectors, 94
afferent fibres, 33
afferent fibres in the ventral root, 50 alleviate pain, 167
allodynia, 155 amputated, 9 amputation, 3 anastomoses, 19 anastomosis of roots, 2 anatomy, 19
angiography, 40, 41 anterolateral approach, 118 apoptotic cell death, 168 apoptotic death, 88 arachnoid, 23 arachnoid cysts, 9 artificial conduits, 170 artificial dura, 132
ascending cervical artery, 25 astrocyte processes, 78 astrocytes, 78
astrocytic fringe, 79 autonomic dysfunction, 174 autonomic system paralysis, 9 avulsion, 7, 114
axon–Schwann cell units, 29 barrier function, 25
basal lamina, 24 BDNF, 90, 168
Bernard–Horner sign, 39
bilateral brachial plexus lesion, 15 bladder contraction, 2
blood supply, 25–27, 35 blood–brain barrier, 100 brachioradial muscle, 45
brain-derived neurotrophic factor, 168 breathing arm phenomenon, 148 bridging channels, 88
Brown–S´equard syndrome, 9, 12, 27, 34, 42, 60
Bugner, 83 bypass grafts, 130 C5, 20, 21 C6, 20, 21 C7, 20, 21 C8, 20, 21
calcitonin gene-related peptide, 31 calcium, 168
CAT, 50
catecholaminergic, 84 cauda equina, 3, 11, 21, 114 cell replacement therapy, 169 central cord injury, 34 central mechanism, 13 central motor program, 153 179
cerebrospinal fluid, 24 cervical nerve roots, 27 cervical plexus, 64 cervical spinal cord, 25 cervical spine, 112 CGRP, 31–33 chest X-ray, 52, 65
choline acetyltransferase, 50 cholinergic, 84
chondroitinase enzyme, 170 CNS regeneration, 85 CNS tissue, 170
CNS–PNS borderline, 29 cocontraction, 104–107 cocontractions, 144 collagen, 29 collagen fibres, 99 collateral sprouting, 98 collateral vascular system, 25 combination therapies, 169 combination treatment, 94 computerised tomography, 52 condition lesions, 87
condroitin sulphate proteoglycans (CSPGs), 70
contralateral C7 spinal nerve, 63 controversies, 3
conus medullaris, 167 cordotomy, 34
cortical reorganisation, 155 corticospinal tract, 31 costocervical trunk, 25 cross-innervation, 104 CSF, 24, 120
CT, 52, 55
CT myelogram, 53, 115 CT myelograms, 54 cytokines, 90 deafferentation, 151 decompression, 10
deep transverse vessels, 113 degeneration, 83
delay of repair, 142 dendraxons, 91 dendrites, 90
dendritic tree, 31
denticulate ligaments, 120 dermatomes, 19
descending brainstem pathways, 34 descending inhibitory tracts, 155 dissection, 113
donor-site morbidity, 64 dorsal approach, 116 dorsal columns, 34 dorsal horn, 30, 86 dorsal horn neurons, 150 dorsal root, 12, 14 dorsal root axons, 171 dorsal root entry zone, 24, 27 dorsal root ganglia, 32, 117 dorsal root ganglion, 86–88, 95 dorsal root implantation, 86, 87 DREZ, 24, 27
DRG neurons, 32 dura mater, 25, 120 dural sleeve, 12 electromyography, 102 electrophysiology, 47–50 embryonic, 84
emergency operation, 3 EMG, 102
empty foramen, 114 end-to-side, 64 endoneurial space, 79 endoscopy, 51, 114
epidural venous complexes, 118 epineurium, 11, 25
excitatory postsynaptic potential (EPSP), 104
excitotoxicity, 168
extracellular matrix molecules, 83 extracellular space, 29
extraplexus transfers, 64 extraspinal exposure, 113 femoral nerve, 21, 71–75, 129 fibre tract, 33
fibre tracts, 30, 31 fibronectin, 171
final common pathway, 174
forequarter dislocation, 7 fractures, 41
free-muscle transfer, 71 Galen, Roman physician, 3 GDNF, 88, 89, 168
gene transfer, 94 Glasgow coma score, 58 glia limitans, 79 glia scar, 83
glial cell line–derived neurotrophic factor, 88, 168
glial fringe, 80–82 glutamate, 31, 168 gluteal nerve, 22 glutei muscles, 71
glutei nerves and vessels, 130 gluteus maximus muscle, 130 grey matter, 30
growth factors, 90
growth-associated genes, 142 growth-inhibitory substances, 70 hand function, 46
hemidiaphragm, 52 hemilaminectomy, 120 hemosiderosis, 10 HIF, 100
high-energy trauma, 7 high-speed accident, 38 histochemistry, 50
histological assessment, 50 history, 38
Homer’s Iliad, 38 hypoglossal nerve, 67 hypoxia inducible factor, 100 IGF, 99
iliohypogastricus, 129 ilioinguinalis, 129 imaging, 51
immature animal, 84 implantation, 119 incontinence, 11 infarct, 25
inferior gluteal nerve, 22
inhibitory postsynaptic potential (IPSP), 104
inspection, 39
insulin-like growth factor, 99 intercostal nerve transfers, 65, 66 intercostal nerves, 63
interleukin-6, 89 interneurons, 31
intervertebral canal, 14, 15 intervertebral foramina, 21, 114 intracellular staining, 96 intradural root stumps, 114 intrafusal fibres, 31
intraoperative electrophysiology, 49, 50
intrapelvic exploration, 135 intraplexus transfers, 63, 64 intraspinal exposure, 118 intraspinal plexus injury, 7 irreparable lesions, 64 ischemic cell death, 168 joint arthroscope, 114 Karolinska Hospital, 3, 5 Karolinska Institute, 4 key functions, 64, 160 laminin, 99
laminoplasty, 124
lateral cutaneous nerve of the thigh, 124
lateral exposure, 116 leptomeningeal cells, 99 Lissauer tract, 33 locomotion, 160 locomotor ability, 94 long thoracic nerve, 42, 66 long tract symptoms, 10
longitudinal spinal cord injury, 2, 4 lower trunk, 113
lumbosacral plexus, 47 lumbosacral plexus injury, 10 lumbosacral trunk, 21, 129 macrophages, 100